Raf inhibitor compounds and methods of use thereof

Abstract

Compounds of Formula I are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers, tautomers, prodrugs and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

1 . A compound selected from Formula I: 
       
         
           
           
               
               
           
         
       
       stereoisomers, tautomers, prodrugs and pharmaceutically acceptable salts thereof, wherein:
 the dashed lines represent optional double bonds such that the bicycle containing the double bonds is aromatic; 
 W and Z are independently C or N; 
 X is O, S, NR 6  or CR 6 , and Y is NR 7  or CR 7 ; or X is NR 6  or CR 6 , and Y is O, S, NR 7  or CR 7 ; provided at least one of W, X, Y and Z is other than C, CR 6  and CR 7 ; 
 R 1  and R 2  are independently selected from hydrogen, halogen, CN, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkenyl and C 1 -C 3  alkynyl; 
 R 3  is hydrogen, halogen or C 1 -C 3  alkyl; 
 R 4  is C 3 -C 6  cycloalkyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, phenyl, 3-6 membered heterocyclyl, a 5-6 membered heteroaryl, or NR 8 R 9 , wherein the cycloalkyl, alkyl, alkenyl, alkynyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with OR 20 , halogen, phenyl, C 3 -C 6  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with halogen; 
 R 5  is hydrogen, C 1 -C 3  alkyl optionally substituted by halogen, or NR 10 R 11 ; 
 R 6  is hydrogen, C 1 -C 6  alkoxy or C 1 -C 6  alkyl, wherein each C 1 -C 6  alkoxy and C 1 -C 6  alkyl is optionally substituted with halogen, OR 20 , SR 20 , NR 14 R 15 , C 3 -C 6  cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; provided when X is NR 6  and is double bonded to an adjacent atom in formula I then R 6  is absent; 
 R 7  is hydrogen, C 1 -C 6  alkoxy or C 1 -C 6  alkyl, wherein each C 1 -C 6  alkoxy and C 1 -C 6  alkyl is optionally substituted with halogen, OR 20 , SR 20 , NR 16 R 17 , C 3 -C 6  cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; provided when Y is NR 7  and is double bonded to an adjacent atom in formula I then R 7  is absent; 
 R 8  and R 9  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 8  and R 9  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl, optionally substituted by halogen, oxo or C 1 -C 3  alkyl; 
 R 10  is hydrogen; 
 R 11  is hydrogen, —(C 0 -C 3  alkyl)CN, (C 0 -C 3  alkyl)NR 12 R 13 , (C 0 -C 3  alkyl)OR 20 , (C 1 -C 3  alkyl)SR 20 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 0 -C 3  alkyl)C 3 -C 6  cycloalkyl, (C 0 -C 3  alkyl)phenyl, (C 0 -C 3  alkyl) 3-6-membered heterocyclyl or (C 0 -C 3  alkyl) 5-6-membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl are optionally substituted by halogen, oxo, OR 21 , NR 18 R 19  or C 1 -C 3  alkyl; 
 R 12  and R 13  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 12  and R 13  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl, optionally substituted by halogen, oxo or C 1 -C 3  alkyl; 
 R 14  and R 15  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 14  and R 15  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 3  alkyl; 
 R 16  and R 17  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 16  and R 17  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 3  alkyl; 
 R 18  and R 19  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 18  and R 19  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 3  alkyl; 
 each R 20  is independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; and 
 each R 21  is independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen. 
 
     
     
         2 . A compound of  claim 1  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1 , wherein W and Z are C, X is S and Y is CR 7 . 
     
     
         4 . A compound of  claim 1 , wherein W and Z are C, X is NR 6  and Y is CR 7 . 
     
     
         5 . A compound of  claim 1 , wherein W and Z are C, X is NR 6  and Y is N. 
     
     
         6 . A compound of  claim 1 , wherein W and Z are C, X is CR 6  and Y is S. 
     
     
         7 . A compound of  claim 1 , wherein W and Z are C, X is CR 6  and Y is NR 7 . 
     
     
         8 . A compound of  claim 1 , wherein W and Z are C, X is N and Y is S. 
     
     
         9 . A compound of  claim 1 , wherein W is N, Z is C, X is CR 6  and Y is CR 7 . 
     
     
         10 . A compound of  claim 1 , wherein W is C, Z is N, X is CR 6  and Y is CR 7 . 
     
     
         11 . A compound of  claim 1 , wherein W is N, Z is C, X is N and Y is CR 7 . 
     
     
         12 . A compound of  claim 1 , wherein W is C, Z is N, X is CR 6  and Y is N. 
     
     
         13 . A compound of  claim 1 , wherein W is N, Z is C, X is CR 6  and Y is N. 
     
     
         14 . A compound of  claim 1 , wherein W and Z are C, X is S and Y is N. 
     
     
         15 . A compound of  claim 1 , wherein W is C, Z is N, X is N and Y is CR 7 . 
     
     
         16 . A compound of  claim 1 , wherein W and Z are C, X is CR 6  and Y is S. 
     
     
         17 . A compound of any one of  claims 1 - 16 , wherein R 1 , R 2  and R 3  are independently selected from hydrogen, halogen or C 1 -C 3  alkyl. 
     
     
         18 . A compound of any one of  claims 1 - 17 , wherein R 1  and R 2  are F or Cl and R 3  is hydrogen. 
     
     
         19 . A compound of any one of  claims 1 - 18 , wherein R 1  is Cl, and R 2  is F and R 3  is hydrogen. 
     
     
         20 . A compound of any one of  claims 1 - 19 , wherein R 4  is C 1 -C 3  alkyl optionally substituted by halogen. 
     
     
         21 . A compound of any one of  claims 1 - 20 , wherein R 4  is ethyl, propyl or —CH 2 CH 2 CH 2 F. 
     
     
         22 . A compound of any one of  claims 1 - 21 , wherein R 5  is NR 10 R 11 . 
     
     
         23 . A compound of any one of  claims 1 - 21 , wherein R 5  is NH 2 . 
     
     
         24 . A compound named in any one of Examples 1-113. 
     
     
         25 . A pharmaceutical composition, comprising a compound of any one of  claims 1 - 24  and  30  and a pharmaceutically acceptable carrier or excipient. 
     
     
         26 . A method of preventing or treating a disease or disorder modulated by b-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of any one of  claims 1 - 24  and  30 . 
     
     
         27 . A compound of any one of  claims 1 - 24  and  30  for use in therapy. 
     
     
         28 . Use of a compound of any one of  claims 1 - 24  and  30  in the manufacture of a medicament for the treatment of cancer. 
     
     
         29 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 24  and  30  for use in the treatment of cancer. 
     
     
         30 . A compound of  claim 1 , wherein:
 W and Z are independently C or N;   X is O, S, NR 6  or CR 6 , and Y is NR 7  or CR 7 ; or X is NR 6  or CR 6 , and Y is O, S, NR 7  or CR 7 ; provided at least one of W, X, Y and Z is other than C, CR 6  and CR 7 ;   R 1  and R 2  are independently selected from hydrogen, halogen, CN, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkenyl and C 1 -C 3  alkynyl;   R 3  is hydrogen, halogen or C 1 -C 3  alkyl;   R 4  is C 3 -C 5  cycloalkyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, phenyl, a 5-6 membered heteroaryl, or NR 8 R 9 , wherein the cycloalkyl, alkyl, alkenyl, alkynyl, phenyl and heteroaryl are optionally substituted with OR 20 , halogen, phenyl, C 3 -C 4  cycloalkyl, or C 1 -C 4  alkyl optionally substituted with halogen;   R 5  is hydrogen, C 1 -C 3  alkyl, or NR10R11;   R 6  is hydrogen, C 1 -C 6  alkoxy or C 1 -C 6  alkyl, wherein each C 1 -C 6  alkoxy and C 1 -C 6  alkyl is optionally substituted with halogen, OR 20 , SR 20 , NR 14 R 15 , C 3 -C 6  cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; provided when X is NR 6  and is double bonded to an adjacent atom in formula I then R 6  is absent;   R 7  is hydrogen, C 1 -C 6  alkoxy or C 1 -C 6  alkyl, wherein each C 1 -C 6  alkoxy and C 1 -C 6  alkyl is optionally substituted with halogen, OR 20 , SR 20 , NR 16 R 17 , C 3 -C 6  cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; provided when Y is NR 7  and is double bonded to an adjacent atom in formula I then R 7  is absent;   R 8  and R 9  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 8  and R 9  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl, optionally substituted by halogen, oxo or C 1 -C 3  alkyl;   R 10  is hydrogen;   R 11  is hydrogen, —(C 0 -C 3  alkyl)CN, (C 0 -C 3  alkyl)NR 12 R 13 , (C 0 -C 3  alkyl)OR 20 , (C 1 -C 3  alkyl)SR 20 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 0 -C 3  alkyl)C 3 -C 6  cycloalkyl, (C 0 -C 3  alkyl)phenyl, (C 0 -C 3  alkyl) 3-6-membered heterocyclyl or (C 0 -C 3  alkyl) 5-6-membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl are optionally substituted by halogen, oxo, OR 21 , NR 18 R 19  or C 1 -C 3  alkyl;   R 12  and R 13  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 12  and R 13  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl, optionally substituted by halogen, oxo or C 1 -C 3  alkyl;   R 14  and R 15  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 14  and R 15  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 3  alkyl;   R 16  and R 17  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 16  and R 17  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 3  alkyl;   R 18  and R 19  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; or R 18  and R 19  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 3  alkyl;   each R 20  is independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen; and   each R 21  is independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen.